Method for treating premature ejaculation with a botulinum neurotoxin

ABSTRACT

Methods for prolongation of climax time in a patient in need thereof are presented, as are methods for treating premature ejaculation by local administration of a Clostridial neurotoxin, such a  botulinum  neurotoxin, to the patient, are provided.

BACKGROUND

Methods for treating premature ejaculation are presented. Moreparticularly and in one aspect, methods for treating prematureejaculation by administration of a neurotoxin, such a botulinumneurotoxin, to a patient are provided.

Premature ejaculation (PE) is a common sexual dysfunction in men,particularly those in the age range of about 18 to about 40 years old.Premature ejaculation can be generally defined as the occurrence ofejaculation prior to or sooner than hoped for by one or both sexualpartners [e.g. see ‘The Merck Manual’, 16^(th) Edition, p 1576,published by Merck Research Laboratories, 1992]. As one example,premature ejaculation can be experienced as ejaculation before, upon orshortly after penile penetration of a sexual partner. If the instancesof premature ejaculation are few and far between, then such occurrencesmay not be a cause for concern. However, if instances of prematureejaculation occur practically every time intercourse is attempted, oreven if premature ejaculation occurs even greater than about 10% orabout 20% of the time intercourse is attempted, then treatment of thecondition is likely to be warranted.

Premature ejaculation may be classified as primary or secondary, inaccordance with the Diagnostic and Statistical Manual of MentalDisorders, Fourth Edition (DSM-IV), which classifies sexual disordersinto 4 particular categories: (1) primary, (2) general medicalcondition-related, (3) substance-induced, and (4) not otherwisespecified. Primary applies to individuals who have had the conditionsince they became capable of functioning sexually (ie, postpuberty).Secondary indicates that the condition manifests itself in an individualwhere an acceptable level of ejaculatory control was previously had, andthen began to experiencing premature ejaculation thereafter. Withsecondary premature ejaculation, the problem does not relate to ageneral medical disorder, and it is usually not related to substanceinducement, however, hyperexcitability might in particular instancesrelate to psychotropic drug use and resolves when the drug is withdrawn.

The prevalence rate of premature ejaculation in American males isestimated to range from 30-70%. The National Health and Social LifeSurvey (NHSLS) indicates a prevalence of 30%, which is fairly steadythrough all adult age categories. Premature ejaculation can occur atvirtually any age in an adult man's life. As a reported condition, it ismost common in younger men (aged 18-30 years old) but may also occur inconjunction with secondary impotence in men aged 45-65 years.

Compositions that can be utilized for treating premature ejaculation areknown. For example, use of selective serotonin reuptake inhibitors(SSRI's) for treating premature ejaculation are known and claimed, forexample, in U.S. Pat. No. 7,105,516 which is directed to novel SSRI'seffective for the treatment of premature ejaculation, as well as U.S.Pat. No. 6,777,437. Additional methods for treating prematureejaculation can be found in U.S. Pat. No. 6,974,839, which teachesadministration of an effective amount of a tramadol (a monoamine uptakeinhibitor) material to a male prior to sexual intercourse, and in U.S.Pat. No. 6,495,154, which claims delaying the onset of ejaculation in amale by systemically administering to the individual a rapid-releasepharmaceutical formulation containing clomipramine and pharmacologicallyacceptable acid addition salts thereof. U.S. Pat. No. 7,018,648 isdirected to a transdermal device for administering testosterone and/orat least one derivative thereof to treat premature ejaculation; U.S.Pat. No. 6,593,335 is directed to method of treating prematureejaculation by administration of a potassium channel opener; U.S. Pat.No. 6,727,283 discloses oral ingestion of an essentially nonaqueous,liquid concentrate of sertraline hydrochloride. In some examples,fluoxetine or paroxetine, (20 mg and 40 mg, respectively, and takendaily) are also prescribed in order to treat premature ejaculation.Other approaches that are known include application of topicalanesthetics, such as lidocaine 5% cream, for example, to the penisbefore intercourse. Drawbacks associated with the use such anestheticsinclude undesired reduction in sensitivity and/or short term inabilityof the patient to achieve an erection.

The anaerobic, gram positive bacterium Clostridium botulinum produces apotent polypeptide neurotoxin, botulinum neurotoxin, which causes aneuroparalytic illness in humans and animals referred to as botulism,however this neurotoxin has now been utilized for decades for treatingvarious conditions in human beings. One unit (U) of botulinum toxin isdefined as the LD₅₀ upon intraperitoneal injection into female SwissWebster mice weighing 18-20 grams each. In other words, one unit ofbotulinum toxin is the amount of botulinum toxin that kills 50% of agroup of female Swiss Webster mice. Seven generally immunologicallydistinct botulinum neurotoxins have been characterized, these beingrespectively botulinum neurotoxin serotypes A, B, C₁, D, E, F, and G,each of which is distinguished by neutralization with type-specificantibodies. The different serotypes of botulinum toxin vary in theanimal species that they affect and in the severity and duration of theparalysis they evoke. For example, it has been determined that botulinumtoxin type A is 500 times more potent, as measured by the rate ofparalysis produced in the rat, than is botulinum toxin type B.Additionally, botulinum toxin type B has been determined to be non-toxicin primates at a dose of 480 U/kg which is about 12 times the primateLD₅₀ for botulinum toxin type A. The botulinum toxins apparently bindwith high affinity to cholinergic motor neurons, are translocated intothe neuron and block the presynaptic release of acetylcholine.

Botulinum toxins have been used in clinical settings for the treatmentof neuromuscular disorders characterized by hyperactive skeletalmuscles. Botulinum toxin type A was approved by the U.S. Food and DrugAdministration in 1989 for the treatment of essential blepharospasm,strabismus and hemifacial spasm in patients over the age of twelve. In2000 the FDA approved commercial preparations of type A and type Bbotulinum toxin serotypes for the treatment of cervical dystonia, and in2002 the FDA approved a type A botulinum toxin for the cosmetictreatment of certain hyperkinetic (glabellar) facial wrinkles. Clinicaleffects of peripheral intramuscular botulinum toxin type A are usuallyseen within one week of injection and sometimes within a few hours. Thetypical duration of flaccid muscle paralysis from a single intramuscularinjection of botulinum toxin type A can be about three months, althoughin some cases the effects of a botulinum toxin induced denervation of agland, such as a salivary gland, have been reported to last for severalyears.

Although all the botulinum toxins serotypes apparently inhibit releaseof the neurotransmitter acetylcholine at the neuromuscular junction,they do so by affecting different neurosecretory proteins and/orcleaving these proteins at different sites. Botulinum toxin A is a zincendopeptidase which can specifically hydrolyze a peptide linkage of theintracellular, vesicle associated protein SNAP-25. Botulinum type E alsocleaves the 25 kiloDalton (kD) synaptosomal associated protein(SNAP-25), but targets different amino acid sequences within thisprotein, as compared to botulinum toxin type A. Botulinum toxin types B,D, F and G act on vesicle-associated protein (VAMP, also calledsynaptobrevin), with each serotype cleaving the protein at a differentsite. Finally, botulinum toxin type C₁ has been shown to cleave bothsyntaxin and SNAP-25.

Regardless of serotype, the molecular mechanism of toxin intoxicationappears to be similar and to involve at least three steps or stages. Inthe first step of the process, the toxin binds to the presynapticmembrane of the target neuron through a specific interaction between theheavy chain (H chain) and a cell surface receptor; the receptor isthought to be different for each serotype of botulinum toxin and fortetanus toxin. The carboxyl end segment of the H chain, Hc, appears tobe important for targeting of the toxin to the cell surface. In thesecond step, the toxin crosses the plasma membrane of the poisoned cell.The toxin is first engulfed by the cell through receptor-mediatedendocytosis, and an endosome containing the toxin is formed. The toxinthen escapes the endosome into the cytoplasm of the cell. This last stepis thought to be mediated by the amino end segment of the H chain, HN,which triggers a conformational change of the toxin in response to a pHof about 5.5 or lower. Endosomes are known to possess a proton pumpwhich decreases intra endosomal pH. The conformational shift exposeshydrophobic residues in the toxin, which permits the toxin to embeditself in the endosomal membrane. The toxin then translocates throughthe endosomal membrane into the cytosol. The last step of the mechanismof botulinum toxin activity appears to involve reduction of thedisulfide bond joining the H and L chain. The entire toxic activity ofbotulinum and tetanus toxins is contained in the L chain of theholotoxin; the L chain is a zinc (Zn++) endopeptidase which selectivelycleaves proteins essential for recognition and docking ofneurotransmitter-containing vesicles with the cytoplasmic surface of theplasma membrane, and fusion of the vesicles with the plasma membrane.Tetanus neurotoxin, botulinum toxin B, D, F, and G cause degradation ofsynaptobrevin (also called vesicle-associated membrane protein (VAMP)),a synaptosomal membrane protein. Most of the VAMP present at thecytosolic surface of the synaptic vesicle is removed as a result of anyone of these cleavage events. Each toxin specifically cleaves adifferent bond.

The molecular weight of the botulinum toxin protein molecule, for allseven of the known botulinum toxin serotypes, is about 150 kDa.Interestingly, the botulinum toxins are released by Clostridialbacterium as complexes comprising the 150 kD botulinum toxin proteinmolecule along with associated non-toxin proteins. Thus, the botulinumtoxin type A complex can be produced by Clostridial bacterium as 900kDa, 500 kDa and 300 kDa forms. Botulinum toxin types B and C₁ areapparently produced as only a 500 kDa complex. Botulinum toxin type D isproduced as both 300 kDa and 500 kDa complexes. Finally, botulinum toxintypes E and F are produced as only approximately 300 kDa complexes. Thecomplexes (i.e. molecular weight greater than about 150 kDa) arebelieved to contain a non-toxin hemaglutinin protein and a non-toxin andnon-toxic nonhemaglutinin protein. These two non-toxin proteins (whichalong with the botulinum toxin molecule can comprise the relevantneurotoxin complex) may act to provide stability against denaturation tothe botulinum toxin molecule and protection against digestive acids whentoxin is ingested. Additionally, it is possible that the larger (greaterthan about 150 kDa molecular weight) botulinum toxin complexes mayresult in a slower rate of diffusion of the botulinum toxin away from asite of intramuscular injection of a botulinum toxin complex. The toxincomplexes can be dissociated into toxin protein and hemagglutininproteins by treating the complex with red blood cells at pH 7.3. Thetoxin protein has a marked instability upon removal of the hemagglutininprotein.

All the botulinum toxin serotypes are made by Clostridium botulinumbacteria as inactive single chain proteins which must be cleaved ornicked by proteases to become neuroactive. The bacterial strains thatmake botulinum toxin serotypes A and G possess endogenous proteases andserotypes A and G can therefore be recovered from bacterial cultures inpredominantly their active form. In contrast, botulinum toxin serotypesC₁, D, and E are synthesized by nonproteolytic strains and are thereforetypically unactivated when recovered from culture. Serotypes B and F areproduced by both proteolytic and nonproteolytic strains and thereforecan be recovered in either the active or inactive form. However, eventhe proteolytic strains that produce, for example, the botulinum toxintype B serotype only cleave a portion of the toxin produced. The exactproportion of nicked to unnicked molecules depends on the length ofincubation and the temperature of the culture. Therefore, a certainpercentage of any preparation of, for example, the botulinum toxin typeB toxin is likely to be inactive, possibly accounting for a lowerpotency of botulinum toxin type B as compared to botulinum toxin type A.The presence of inactive botulinum toxin molecules in a clinicalpreparation will contribute to the overall protein load of thepreparation, which has been linked to increased antigenicity, withoutcontributing to its clinical efficacy.

In vitro studies have indicated that botulinum toxin inhibits potassiumcation induced release of both acetylcholine and norepinephrine fromprimary cell cultures of brainstem tissue. Additionally, it has beenreported that botulinum toxin inhibits the evoked release of bothglycine and glutamate in primary cultures of spinal cord neurons andthat in brain synaptosome preparations botulinum toxin inhibits therelease of each of the neurotransmitters acetylcholine, dopamine,norepinephrine, CGRP and glutamate.

High quality crystalline botulinum toxin type A can be produced from theHall A strain of Clostridium botulinum with characteristics of ≧3×10⁷U/mg, an A₂₆₀/A₂₇₈ of less than 0.60 and a distinct pattern of bandingon gel electrophoresis. The known Shantz process can be used to obtaincrystalline botulinum toxin type A, as set forth in Shantz, E. J., etal, Properties and use of Botulinum toxin and Other MicrobialNeurotoxins in Medicine, Microbiol Rev. 56: 80-99 (1992). Generally, thebotulinum toxin type A complex can be isolated and purified from ananaerobic fermentation by cultivating Clostridium botulinum type A in asuitable medium. Raw toxin can be harvested by precipitation withsulfuric acid and concentrated by ultramicrofiltration. Purification canbe carried out by dissolving the acid precipitate in calcium chloride.The toxin can then be precipitated with cold ethanol. The precipitatecan be dissolved in sodium phosphate buffer and centrifuged. Upon dryingthere can then be obtained approximately 900 kDa crystalline botulinumtoxin type A complex with a specific potency of 3×10⁷ LD₅₀ U/mg orgreater. This known process can also be used, upon separation out of thenon-toxin proteins, to obtain pure botulinum toxins, such as forexample: purified botulinum toxin type A with an approximately 150 kDamolecular weight with a specific potency of 1-2×10⁸ LD₅₀ U/mg orgreater; purified botulinum toxin type B with an approximately 156 kDamolecular weight with a specific potency of 1-2×10⁸ LD₅₀ U/mg orgreater, and; purified botulinum toxin type F with an approximately 155kDa molecular weight with a specific potency of 1-2×10⁷ LD₅₀ U/mg orgreater.

Already prepared and purified botulinum toxins and toxin complexessuitable for preparing pharmaceutical formulations can be obtained fromList Biological Laboratories, Inc., Campbell, Calif.; the Centre forApplied Microbiology and Research, Porton Down, U.K.; Wako (Osaka,Japan), as well as from Sigma Chemicals of St Louis, Mo.

It has been reported that a botulinum toxin has been used in clinicalsettings as follows:

-   (1) about 75-125 units of BOTOX® per intramuscular injection    (multiple muscles) to treat cervical dystonia;-   (2) 5-10 units of BOTOX® per intramuscular injection to treat    glabellar lines (brow furrows) (5 units injected intramuscularly    into the procerus muscle and 10 units injected intramuscularly into    each corrugator supercilii muscle);-   (3) about 30-80 units of BOTOX® to treat constipation by    intrasphincter injection of the puborectalis muscle;-   (4) about 1-5 units per muscle of intramuscularly injected BOTOX® to    treat blepharospasm by injecting the lateral pre-tarsal orbicularis    oculi muscle of the upper lid and the lateral pre-tarsal orbicularis    oculi of the lower lid.-   (5) to treat strabismus, extraocular muscles have been injected    intramuscularly with between about 1-5 units of BOTOX®, the amount    injected varying based upon both the size of the muscle to be    injected and the extent of muscle paralysis desired (i.e. amount of    diopter correction desired).-   (6) to treat upper limb spasticity following stroke by intramuscular    injections of BOTOX® into five different upper limb flexor muscles,    as follows:

(a) flexor digitorum profundus: 7.5 U to 30 U

(b) flexor digitorum sublimus: 7.5 U to 30 U

(c) flexor carpi ulnaris: 10 U to 40 U

(d) flexor carpi radialis: 15 U to 60 U

(e) biceps brachii: 50 U to 200 U. Each of the five indicated muscleshas been injected at the same treatment session, so that the patientreceives from 90 U to 360 U of upper limb flexor muscle BOTOX® byintramuscular injection at each treatment session.

-   (7) to treat migraine, pericranial injected (injected symmetrically    into glabellar, frontalis and temporalis muscles) injection of 25 U    of BOTOX® has showed significant benefit as a prophylactic treatment    of migraine compared to vehicle as measured by decreased measures of    migraine frequency, maximal severity, associated vomiting and acute    medication use over the three month period following the 25 U    injection.

Additionally, intramuscular botulinum toxin has been used in thetreatment of tremor in patients with Parkinson's disease, although ithas been reported that results have not been impressive. Marjama-Jyons,J., et al., Tremor—Predominant Parkinson's Disease, Drugs & Aging16(4);273-278:2000.

Treatment of certain gastrointestinal and smooth muscle disorders with abotulinum toxin are known. See e.g. U.S. Pat. Nos. 5,427,291 and5,674,205 (Pasricha). Additionally, transurethral injection of abotulinum toxin into a bladder sphincter to treat a urination disorderis known (see e.g. Dykstra, D. D., et al, Treatment ofdetrusor—sphincter dyssynergia with botulinum A toxin: A double—blindstudy, Arch Phys Med Rehabil January 1990;71:24-6), as is injection of abotulinum toxin into the prostate to treat prostatic hyperplasia. Seee.g. U.S. Pat. No. 6,365,164 (Schmidt).

U.S. Pat. No. 5,766,605 (Sanders) proposes the treatment of variousautonomic disorders, such as hypersalivation and rhinittis, with abotulinum toxin.

Furthermore, various afflictions, such as hyperhydrosis and headache,treatable with a botulinum toxin are discussed in WO 95/17904(PCT/US94/14717) (Aoki). EP 0 605 501 B1 (Graham) discusses treatment ofcerebral palsy with a botulinum toxin and U.S. Pat. No. 6,063,768(First) discusses treatment of neurogenic inflammation with a botulinumtoxin. Erectile dysfunction has been reported as a symptom of botulism.Jenzer G., et al., Autonomic dysfunction in botulism B: a clinicalreport, Neurology 1975;25:150-153; Naumann M. et al., Pure autonomicdysfunction in botulism type B, Naunyn Schmiedeberg's Archives ofPharmacology June 2002 (supp 2); 365 (abstract 89 at R31). This may be aresult of circulating botulinum toxin present in a patient with botulismacting to block release of acetylcholine from cholinergicparasympathetic nerve endings in the corpora cavernosa of the penis.This would cause an inhibition of penile smooth muscle relaxation andtherefore a reduced flow of blood into penile structures, and hence aflaccid penis. Contrarily, it has been speculated that a botulinum toxincan be used to cause an erection of the penis. Jones D. Highperformance. Nature 1989;3:348.

It is known that botulinum toxin type A can have an efficacy for up to12 months (European J Neurology 6 (Supp 4): S111-S1150:1999), and insome circumstances for as long as 27 months. The Laryngoscope109:1344-1346:1999. However, the usual duration of an intramuscularinjection of Botox® is typically about 3 to 4 months. The success ofbotulinum toxin type A to treat a variety of clinical conditions has ledto interest in other botulinum toxin serotypes. Additionally, purebotulinum toxin has been used to treat humans. see e.g. Kohl A., et al.,Comparison of the effect of botulinum toxin A (Botox (R)) with thehighly—purified neurotoxin (NT 201) in the extensor digitorum brevismuscle test, Mov Disord 2000;15(Suppl 3):165. Hence, a pharmaceuticalcomposition can be prepared using a pure botulinum toxin.

The botulinum toxin molecule (about 150 kDa), as well as the botulinumtoxin complexes (about 300-900 kDa), such as the toxin type A complexare also extremely susceptible to denaturation due to surfacedenaturation, heat, and alkaline conditions. Inactivated toxin formstoxoid proteins which may be immunogenic. The resulting antibodies canrender a patient refractory to toxin injection. A commercially availablebotulinum toxin containing pharmaceutical composition is sold under thetrademark BOTOX® (available from Allergan, Inc., of Irvine, Calif.).BOTOX® consists of a purified botulinum toxin type A complex, albumin,and sodium chloride packaged in sterile, vacuum-dried form. Thebotulinum toxin type A is made from a culture of the Hall strain ofClostridium botulinum grown in a medium containing N-Z amine and yeastextract. The botulinum toxin type A complex is purified from the culturesolution by a series of acid precipitations to a crystalline complexconsisting of the active high molecular weight toxin protein and anassociated hemagglutinin protein. The crystalline complex isre-dissolved in a solution containing saline and albumin and sterilefiltered (0.2 microns) prior to vacuum-drying. BOTOX® can bereconstituted with sterile, non-preserved saline prior to intramuscularinjection. Each vial of BOTOX® contains about 100 units (U) ofClostridium botulinum toxin type A complex, 0.5 milligrams of humanserum albumin and 0.9 milligrams of sodium chloride in a sterile,vacuum-dried form without a preservative.

To reconstitute vacuum-dried BOTOX® sterile normal saline without apreservative; 0.9% Sodium Chloride injection is used by drawing up theproper amount of diluent in the appropriate size syringe. Since BOTOX®is denatured by bubbling or similar violent agitation, the diluent isgently injected into the vial. BOTOX® should be administered within fourhours after reconstitution. During this time period, reconstitutedBOTOX® is stored in a refrigerator (20 to 8° C.). Reconstituted BOTOX®is clear, colorless and free of particulate matter. The vacuum-driedproduct is stored in a freezer at or below −5° C. BOTOX® is administeredwithin four hours after the vial is removed from the freezer andreconstituted. During these four hours, reconstituted BOTOX® can bestored in a refrigerator (20 to 8° C.).

Other commercially available botulinum toxin containing pharmaceuticalcompositions include Dysport® (Clostridium botulinum type A toxinhaemagglutinin complex with albumin and lactose in the formulation,available from Ipsen Limited, Berkshire, U.K. as a powder to bereconstituted with 0.9% sodium chloride before use), and MyoBloc™ (aninjectable solution comprising botulinum toxin type B, human serumalbumin, sodium succinate, and sodium chloride at about pH 5.6,available from Solstice Neurosciences, Inc).

What is needed therefore is a simple method for treating prematureejaculation and/or prolongation of climax time. In particular, a longlasting, non-systemic method for treating premature ejaculation and/orprolongation of climax time is desired that does not entail oral orrepeated ingestion of a pharmaceutical compound prior to engaging insexual activity.

SUMMARY

The present invention meets this need and provides an effective and longlasting method for treatment for premature ejaculation and/orprolongation of climax time in a patient in need thereof. In one examplea method for treating premature ejaculation in a patient in need thereofis provided, the method comprising the step of locally administering aClostridial neurotoxin to the patient to thereby treat prematureejaculation of the patient. As an example, local administration of atherapeutic amount of Clostridial neurotoxin, in accordance with themethods herein disclosed, is accomplished by transdermal, intramuscular,subcutaneous, subdermal, intradermal or implant administration. In oneembodiment, local administration of a therapeutic amount of Clostridialneurotoxin is by injection into the patient, such as into the penis, forexample. A preferable Clostridial neurotoxin for use in the methodsherein described is a botulinum neurotoxin, which can be selected fromthe group consisting of botulinum neurotoxin types A, B, C, D, E, F andG, and is preferably botulinum neurotoxin type A. Various ranges/amountof botulinum neurotoxin can be therapeutically administered inaccordance with the teachings of the present disclosure, for example,botulinum toxin can be administered in an amount of from about 1 unit to20,000 units, dependent, of course, on the potency of the botulinumtoxin type utilized and its method of administration (e.g. an amount ofbotulinum toxin contained in a slow-release implant or pulsatile implantcan be many times greater than an amount of botulinum toxin that isadministered directly and at once, rather than slowly released from animplant). Exemplary useful amounts for a botulinum neurotoxin type A ortype B, can be from about 1 unit to 2500 units or from about 100 toabout 15,000 units, respectively, or an amount or range therebetween.

In a particular embodiment, local administration of the therapeuticamount of the Clostridial neurotoxin to the patient is accomplished viainjection of the Clostridial neurotoxin into one or more locations of apenis of the patient.

Definitions

-   As used herein, the words or terms set forth below have the    following definitions.-   “About” means approximately or nearly and in the context of a    numerical value or range set forth herein means ±10% of the    numerical value or range recited or claimed.-   “Therapeutically effective amount,” as used herein, means an amount    of a Clostridial neurotoxin, for example a botulinum toxin type A,    B, C, D, E, F and G, that ameliorates, or eliminates one or more    symptoms of a particular disease or condition or prevents or delays    the onset of one or more symptoms of a particular disease or    condition.-   “Local administration” means direct administration by a non-systemic    route at or in the vicinity of the site of an affliction or    disorder. Thus, local administration of a pharmaceutical comprising    a Clostridial neurotoxin, such as a botulinum neurotoxin, excludes    intravenous or oral administration, but includes, for example,    intramuscular, transdermal or subcutaneous injection or placement of    an implant for administration of the neurotoxin.-   “Treating” means to alleviate (or to eliminate) at least one    symptom, either temporarily or permanently. Here, this includes    increasing the time (i.e. prolongation of climax time) it takes a    patient to reach climax after sexual arousal. In a particular    example, climax time is the time between the start of intercourse    and the time at which climax is achieved. The Clostridial toxin is    preferably a botulinum toxin (as either a complex or as a pure toxin    [i.e. about 150 kDa molecule, the neurotoxic component of botulinum    toxin, free of complexing proteins], such as a botulinum toxin A, B,    C, D, E, F or G. Administration of the Clostridial toxin can be via    a transdermal route (e.g. by application of a Clostridial toxin in a    cream, patch or lotion vehicle), subdermal route (i.e. subcutaneous    or intramuscular injection) or by an intradermal route of    administration.-   “Neurotoxin” includes Clostridial neurotoxins both as pure toxin and    complexed with one to more non-toxin, toxin associated proteins,    whether made by the native Clostridial bacterium or by recombinant    means in a non-Clostridial species. “Botulinum neurotoxin” means    non-complexed botulinum neurotoxin (i.e. pure botulinum neurotoxin    molecule having a molecular weight of about 150 kDa) or as a complex    (i.e. having a molecular weight of about 300 to about 900 kDa weight    complex comprising a neurotoxin molecule and one or more associated    non-toxic molecules), and excludes botulinum toxins which are not    neurotoxins such as the cytotoxic botulinum toxins C₂ and C₃, but    can include recombinantly made, hybrid, modified, and chimeric    botulinum toxins.-   “Patient” means a human subject receiving medical care.-   “Climax baseline time” is the pre-treatment climax time of a    patient, that is, the time or average time that it takes for a    patient to climax after becoming sexually aroused.-   “Prolongation of climax time” means an increase in time (increase in    climax baseline time) from which a patient becomes sexually aroused    to the time of sexual climax (i.e. orgasm). In one aspect, “treating    premature ejaculation” means increasing the time between the    beginning of sexual arousal of a patient and ejaculation by the    patient; and in particular instances, it can mean increasing the    time from which sexual intercourse begins to the time of    ejaculation.

The present invention encompasses a method for treating prematureejaculation by local administration of a Clostridial toxin to a mammal,such as a human patient. Preferably, the botulinum toxin is a botulinumtoxin type A. The botulinum toxin can be administered in an amountbetween about 1 unit and about 10,000 units and premature ejaculationand/or prolongation of climax time can be alleviated for between about 2weeks and about 6 months. In particular examples, premature ejaculationand/or prolongation of climax time can be alleviated from about 2 monthsto about 6 months, or from about 4 to about 6 months, for example. Inone aspect, the local administration step is carried out by directadministration of the Clostridial toxin, such as a botulinum neurotoxin,to at least one location of a penis of the patent.

In another embodiment, a method for treating premature ejaculation in apatient in need thereof is provided, where the method comprises a stepof locally administering, by injection, a botulinum neurotoxin to apenis of the patient, thereby treating premature ejaculation in thepatient. In particular embodiments, the botulinum neurotoxin is injectedinto at least two penile locations, and in some examples at least threepenile locaitons. In specific examples, local administration ofbotulinum neurotoxin is to a frenulum of the penis, exemplary amountsbeing from 1 to about 2500 units of a botulinum toxin type A. Whenutilizing a botulinum toxin type B for example, the administered amountcan be from between about 1 unit and about 25,000 units, or from about100 units to about 20,000 units or from about 500 units to about 15,000units or any amount therebetween.

As another example, a method for treating premature ejaculation in apatient in need thereof is herein provided where botulinum neurotoxintype A is locally administered to at least one location of a penis ofthe patient, wherein the location is the frenulum and/or glans of thepenis, to thereby treating premature ejaculation in the patient, whereinexemplary useful amounts include administering to at least the onelocation from about 1 unit to about 2500 units of botulinum neurotoxin.In particular embodiments, additional administration of botulinumneurotoxin to the penis of the patient can be performed, for examplefrom about least about 2 months to about 3 months or more after aninitial administration of botulinum neurotoxin to the penis. Inparticular embodiments, local administration of the botulinum neurotoxintype A is from about 1 unit to about 500 units, per injection site, perpatient visit. Exemplary botulinum neurotoxin administration can be to asingle location on the penis (e.g. frenulum) or distributed over two ormore anatomically distinct portions of the penis (e.g. penile frenulum,penile prepuce/foreskin, glans penis, urethral opening).

Additionally, a method for prolongation of climax time in a patient inneed thereof is provided wherein the method comprises the step oflocally administering a botulinum neurotoxin to the patent to therebyprolong the climax time in the patient. Administration of botulinumneurotoxin can be via transdermal, intramuscular, subcutaneous,subdermal, intradermal or implant administration, and can be to afrenulum or prepuce, for example. In particular embodiments, thebotulinum neurotoxin is administered by injection and the botulinumneurotoxin is botulinum neurotoxin type A or type B.

The age range of patients upon which the methods herein disclosed can bepracticed can be from about 18 year old to about 60 years old, moreparticularly, from about 18 years old to about 40 years old, and evenmore particularly, from about 18 years old to about 30 years old. Inparticular instances, the patient has tried various previous treatmentsthat have not been found to satisfactorily treat the patient's prematureejaculation.

Patients that can be treated by the methods herein disclosed may havepreviously partaken in regimens for treating their premature ejaculationor for prolongation of their climax time. Exemplary regiments caninclude taking a selective serotonin reuptake inhibitor, such asfluoxetine or paroxetine, for example. Other approaches that may havebeen tried include application of topical anesthetics, such as lidocaine5% cream, applied to the penis before intercourse. Such approaches can,if desired, be combined with the methods herein disclosed in order totreat premature ejaculation or for prolongation of climax time.

In particular embodiments the botulinum neurotoxin is administered on anas-needed basis. Dosing will be determined for, and be particular to,the patient/particular presentation of premature ejaculation, withnon-limiting, exemplary amounts provided herein. Duration of effectafter botulinum administration can be up to about 4 months afteradministration, for example. In particular instances, the duration ofeffect after botulinum administration can be from about 2 days to about3 months after botulinum administration. Shorter duration of effects canbe associated with a botulinum toxin having a short actingprofile/duration of effect, such as botulinum toxin type E, relative toanother botulinum toxin, such as a botulinum toxin type A, for example.

DESCRIPTION

Methods for treating premature ejaculation are herein provided, bylocally administering a Clostridial toxin, preferably a botulinum toxinselected from the group consisting of botulinum toxin type A, B, C, D,E, F and G, more preferably botulinum toxin type A or B, most preferablybotulinum toxin type A, to a patient in need thereof. Methods hereindisclosed provide patients the ability to prolong climax time and/ortreat premature ejaculation via a safe, easy, long lasting treatmentmethod that can have a duration of desired effect for up to about 6months.

There are several useful ways by which the Clostridial toxin may belocally administered. For example, transdermal methods for administeringa botulinum toxin are known in the art, utilizing various botulinumformulations. Such formulations can be water-based, as currentlyavailable commercial forms of botulinum toxin are diluted with, orsupplied in, saline. However, other aqueous or non-aqueous deliverycarriers, such as creams, lotions, gels, ointments, or emulsions arealso contemplated (for transdermal administration of botulinum toxinssee, for example the following non-exhaustive list: United States PatentApplication No. 20040009180, filed Jul. 11, 2002 entitled “Transdermalbotulinum toxin compositions”; United States Patent Application No.20090087457, filed Mar. 3, 2006 entitled “Compositions and Methods forTopical Application and Transdermal Delivery of Botulinum Toxins”;United States Patent Application No. 20070116724 filed Nov. 16, 2006entitled “Compositions and Methods of Topical Application andTransdermal Delivery of Botulinum Toxins without Reduced Non-ToxinProteins”; United States Patent Application No. 20030113349, filed Dec.18, 2002 entitled “Topically applied clostridium botulinum toxincompositions and treatment methods”; U.S. Patent Application No.20080220021, filed May 23, 2008 entitled “Topical Botulinum ToxinCompositions for the Treatment of Hyperhidrosis”; WIPO Publication No.WO/2008/070538, filed Nov. 30, 2007 entitled “Micellar NanoparticlesComprising Botulinum Toxin” and U.S. Pat. No. 7,445,783 entitled“Topical and transdermal treatments using urea formulations”, all suchpatents and patent applications are herein incorporated by reference intheir entirety.

The present invention includes within its scope: (a) a botulinumneurotoxin complex as well as a pure botulinum neurotoxin obtained orprocessed by bacterial culturing, toxin extraction, concentration,preservation, freeze drying and/or reconstitution and; (b) modified orrecombinant botulinum neurotoxin, that is botulinum neurotoxin that hashad one or more amino acids or amino acid sequences deliberatelydeleted, modified or replaced by known chemical/biochemical amino acidmodification procedures or by use of known host cell/recombinant vectorrecombinant technologies, as well as derivatives or fragments ofbotulinum neurotoxins so made, and includes botulinum neurotoxins withone or more attached non-native targeting moieties for a cell surfacereceptor present on a cell.

Preferably, because of its clinical history to successfully treat anumber of indications, a method within the scope of the presentinvention includes local administration of a botulinum type A orbotulinum toxin type B, although botulinum toxin type B is used with alarger protein load, as compared to type A toxin. A botulinum toxin typeA used in a method within the scope of the present invention can be acomplex of toxin and non-toxin proteins, which together comprise a totalmolecular weight of up to about 900 kDa. Dosage ranges and amounts, likeany pharmaceutical, are based upon size, age and health of the patient,as well as upon the particular commercial preparation of the botulinumtoxin used. As known in the art, therapeutic use of botulinum toxins istailored to the particular patient that is presented for treatment, e.g.to treat premature ejaculation. A botulinum toxin type B used in amethod within the scope of the present invention can be a pure toxin orcomplex of toxin and non-toxin proteins, which is used at a dose ofbetween about 50 and about 20,000 units. Other botulinum toxin serotypesmay be used in proportion to the dosages and concentrations exemplifiedherein, according to their respective levels of biological activity. Forexample, most units listed in the instant disclosure are of BOTOX®, butdifferent serotypes or strains of a botulinum toxin may be used, anddifferent amounts may be administered. For example, about 3-4 times ofDYSPORT® (a botulinum toxin type A complex available from Ipsen Inc.)than an amount of BOTOX® may be utilized; about 40-50 times ofNEUROBLOC®/MYOBLOC® (a botulinum toxin type B available from SolsticeNeurosciences) than an amount of BOTOX® may be utilized; and aboutequivalent amounts, in units, of XEOMIN® (pure botulinum toxin type A,by Merz Pharma) relative to BOTOX® units can be utilized, to achieve adesired therapeutic effect, respectively. The present invention alsoencompasses methods for concurrent or serial administration of a mixtureof two or more of the above neurotoxins to effectively treat a patientwith premature ejaculation.

In addition to transdermal methods for administering a botulinum toxin,injection of a botulinum toxin can be utilized to treat prematureejaculation and/or for prolongation of climax time. When injections areutilized, an appropriate needle for botulinum toxin injection can beutilized, such as, but are not limited to needles of 30-guage orsmaller, preferably from about 23-gauge to about 25-gauge, and the areais preferably cleaned, such as with alcohol, before injection. Localanesthetic cream, general anesthesia, sedation or any known be usefulanesthetic may be utilized, and may be necessary, depending upon theparticular patient (some patients being more sensitive than others)undergoing treatment in accordance with the present methods. Inparticular examples, topical use of an anesthetic cream, such as, forexample benzocaine, butamben, dibucaine, lidocaine, oxybuprocaine,pramoxine, proparacaine, proxymetacaine, and tetracaine can be appliedbefore administration of the botulinum toxin via a needle. Additionally,needleless administration methods for delivery of botulinum toxins arewell known in the art (see for example, U.S. Pat. Nos. 7,479,281 and7,479,134 both herein incorporated by reference), and suchadministration/apparatus can be utilized as a delivery means foradministration of botulinum toxin in accordance with the treatmentmethods herein disclosed.

In particular examples, topical lidocaine anesthetic cream is utilizedand applied to the area to be injected. Other anesthetic methods can beutilized, such as blockade of the penile branches of the prudendalnerve, utilizing, for example, a 2% lidocaine injection (from about 5 ccto about 10 cc total of a 2% lidocaine preparation) administered to thebase of the penis (to the anterior (ventral) and posterior (dorsal) ofthe base of the penis); and/or sometimes cooling of the area to beinjected may be utilized, such as by the application of ice or cold air(cold air can be applied utilizing a “Zimmer Cryo 5” apparatus fromZimmer Medizin Systems, Irvine, Calif., for example).

The amount of the neurotoxin, such as a botulinum toxin, administeredcan vary widely according to the particular patient/case being treated,its severity and other various patient variables including size, weight,age, and patient responsiveness to therapy. Generally, the dose ofbotulinum neurotoxin to be administered will vary with the age, size andpresenting condition of the patient to be treated. When therapeuticallyutilizing botulinum toxins, the potency of the neurotoxin to beadministered is also a consideration (tailoring a particular dosage ofbotulinum toxin to a particular patient/case is well known in thebotulinum neurotoxin arts).

In some instances, the dosage of botulinum neurotoxin administered canbe increased until achieving the desired effect (e.g. until the patientis satisfied with the resultant delay in ejaculation). In a particularembodiment, a first dosage can be from about 10 units to about 75 unitsof a botulinum toxin, or from about 25 units to about 50 units of abotulinum toxin, such as BOTOX®. If unsatisfactory results are observed,treatment dosage can be increased, as determined by the medicalpractitioner's evaluation of the particular case at hand, the dosage,for example, being increased up to about 100 units of a botulinum toxin.In such instances, the time between administration of increasing dosagesof botulinum toxin can be about 3 weeks, preferably about 1 month andmost preferably about 2 months.

The present methods for treating premature ejaculation and/orprolongation climax time can be practiced, for example, on patient ofabout 18 years old to about 60 years old, more particularly, from about18 years old to about 40 years old, and even more particularly, fromabout 18 years old to about 30 years old. In any such patient, theproblem of premature ejaculation can present itself as when the patientis not being able to abstain from ejaculation for a sufficient time asdesired. For example, a patient may experience a “climax base time”,that is, the time or average time that it takes for the patient toclimax after becoming sexually aroused, of from about 1 minute to about10 minutes. In particular instances, this may not even allow the patientto begin/achieve sexual intercourse if the patient prematurelyejaculates before even beginning sexual intercourse (e.g. before penilepenetration of partner), or results in ejaculation instantly upon penilepenetration or even attempting penetration. Clearly a patient thatsuffers from such a predicament would be well served by the treatmentmethods herein disclosed.

In some instances premature ejaculation can be experienced even afterthe beginning of sexual intercourse, that this, even if a patient isable to penetrate their partner (i.e. not ejaculate prior topenetration), ejaculation prematurely follows. In such instances, it isthe time period between penetration and ejaculation that considered tobe too short, and accordingly prolongation of climax time, hereincreasing the time from which sexual intercourse begins to the time ofejaculation, is desired. In particular non-limiting examples, a patientmay be considered to suffer from premature ejaculation if ejaculation isachieved after from about 10 seconds to about 15 minutes afterpenetration, from about 15 seconds to about 10 minutes after penetrationor from about 30 seconds to about 5 minutes after penetration. Inparticular cases, a patient may be considered to suffer from prematureejaculation if ejaculation is achieved after from about 10 seconds toabout 3 minutes after penetration, from about 25 seconds to about 2minutes after penetration or from about 30 seconds to about 1 minuteafter penetration.

Patients suffering from premature ejaculation may have found thatprevious treatment methods, such as ingestion of SSRIs (e.g. fluoxetineor paroxetine, 20 mg and 40 mg respectively and taken daily) did notsufficiently treat their premature ejaculation and thus will find theinstant treatment methods to be useful, either in place of theirselective serotonin reuptake inhibitor regimen or in conjunction withsuch a regimen. Previously undertaken approaches which may not haveprovided satisfactory results can also include use of topical anesthetictherapy, such as the application of a 5% lidocaine cream to a penis forexample, prior to (e.g. about 10 minutes before) intercourse. Thepatient utilizing topical anesthetic therapy may find the instanttreatment methods to be useful either in place of their topicalanesthetic therapy regimen or in conjunction with a topical anesthetictherapy regimen.

Exemplary locations at which a botulinum toxin, such as botulinum toxintype A or B, may be administered include the penis. In particular, areassuch as the glans, balonopreputial surface, frenulum, alone or in anycombination for example, can be targeted for administration of abotulinum neurotoxin in order to treat premature ejaculation.

In exemplary embodiments, the area that is to receive the botulinumneurotoxin is cleaned utilizing alcohol, such as by utilizing an alcoholwipe, for example. If desired, local anesthetic (as disclosed herein) isthen applied to the cleaned area, after which the botulinum neurotoxinis administered. Post-procedurally, the patient is instructed not toengage in sexual activity for the following 48 hours, and if edemaand/or inflammation is observed, a cold compress or ice pack may beapplied. Typically, patients observe effects (e.g. delaying ofpreviously premature ejaculation) within about 48 to about 72 hours,with full results (maximum delay) usually observed after about 3 weeks.The following are non-limiting examples where patient's suffering frompremature ejaculation are treated.

EXAMPLES Example 1 Treatment of Premature Ejaculation

A 24 year old male presents at his doctor's office complaining that heclimaxes within about 2 minutes after penetration of his partner (forthis patient, his climax baseline time is 2 minutes). This is a subjectof great consternation to the patient as well as his partner. The doctortreats the patient by cleaning the area to be injected with isopropylalcohol and administering about 50 units of a botulinum toxin type A(BOTOX®) to the patient's penis, using a 30 gauge needle. Injection isinto the glans of the penis and about 1 cm from the urethral opening andthe patient is instructed to not have sex for 48 hours. At a follow-upvisit, the patient reports experiencing a slight pain at the site ofinjection that disappeared within 24 hours of the injection, butotherwise no erectile dysfunction or loss of sensitivity is noted. Thepatient reports that he has doubled his climax baseline time (from about2 to about 4 minutes), and frequently is even able to enjoy intercoursefor longer than 4 minutes (greater than doubling his climax baselinetime). These results, that is, prolonging the time this patientejaculates after the start of intercourse, are observed for about 4months after initial botulinum neurotoxin administration, after whichthe patient returns for re-injection of the same amount of botulinumtoxin at the same location.

It is noted that in this instance, the doctor may have chosen toadminister another botulinum preparation/serotype, if he so chooses,such as, for example, about 200 units of DYSPORT or about 50 units ofXEOMIN (botulinum toxin type A preparations) or about 2500 units ofMYOBLOC (botulinum toxin type B preparation).

Example 2 Treatment of Premature Ejaculation

A 32 year old male presents at his doctor's office complaining thatevery instance he engages in sexual intercourse, he climaxes withinabout 10 seconds after penetration of his partner (his climax baselinetime is about 10 seconds), a situation that both the patient and hispartner are growing quite tired of. Accordingly and after taking adetailed sexual history of the patient, the doctor determines that thepatient is suffering from premature ejaculation and decides toadminister botulinum neurotoxin to the patient. Accordingly, the doctorcleans the patient's penile frenulum over the anterior region of theglans with isopropyl alcohol and subsequently applies topical lidocaineanesthesia cream to anesthetize the area, after which 25 units of abotulinum neurotoxin (BOTOX®) is injected, utilizing a 25 gauge needle.Post procedure, the patient is instructed not to have sex during thefollowing 48 hours. If edema and/or inflammation is noted, appropriateapplication of an ice-pack to the area is recommended (applied notlonger than about 15 minutes at a time).

At a follow up session 2 weeks later, the patient reports that he isstill unable to withhold ejaculation for greater than about 10 seconds.Accordingly, the doctor prepares the patient as before for theinjection, this time administering 50 units of a botulinum neurotoxin(BOTOX®) and sends the patient along with the same post-procedureinstructions. At a follow up session 3 weeks later, the patient reportsa doubling in his climax baseline time, with on some occasions lastingfor about 10 to 15 minutes, and that both he and his partner are verysatisfied with the resultant outcome of the treatment.

Example 3 Treatment of Primary Premature Ejaculation

After suffering for decades, a 42 year old male visits his doctorsoffice to report that his suffering from premature ejaculation precludeshis ability to have sexual intercourse, since once sexually aroused, heprematurely ejaculates before even commencing with intercourse. Heinforms the doctor that he has been this way ever since reaching sexualmaturity. His physician decides to prescribe fluoxetine 20 mg, takendaily to see if this will help mitigate his primary prematureejaculation. After 2 months of taking the fluoxetine, the patientreports no change in his premature ejaculation before commencingintercourse. In addition to the daily fluoxetine, topical therapy isprescribed, in particular the patient is instructed to topically apply a5% lidocaine cream about 10 minutes before intercourse. Three weekslater, the patient still reports no change in his situation.

The physician decides to administer a botulinum neurotoxin to thepatient's penis. Accordingly, the area of the posterior region of theglans in the balonopreputial surface and the frenulum is cleaned withalcohol and a prudendal nervous blockade is applied, utilizing a 2%lidocaine injection to the dorsal and ventral portion of the penis base(the blockade administration of anesthetic being as utilized/similar toadministration for a male circumcision, for example). About 50 units ofbotulinum toxin type A (BOTOX) is injected into the posterior region ofthe glans in the balonopreputial area and another 25 units isadministered to the fremulum. Post procedure, the patient is instructednot to have sex during the following 48 hours. If edema and/orinflammation is noted, appropriate application of an ice-pack to thearea is recommended (not longer than about 15 minutes at a time), andthe patient is instructed to continue with the fluoxetine. The patientreports back 2 weeks later that he is now able to penetrate and haveintercourse with his partner for up to about 15 minutes withoutprematurely ejaculating, and these positive result are observed forabout 3 months.

Example 4 Treatment of Secondary Premature Ejaculation

A 52 year old man presents at his doctor's office complaining that he issuffering from premature ejaculation. The patient informs the doctorthat he previously has not suffered from this condition, however eversince he has become sexually involved with his latest partner, he hasnot been able to avoid episodes of premature ejaculation. The doctordecides to treat the patient by administering 2500 units of botulinumtoxin type B (MYOBLOC®) to the frenulum of the patient. After injection,the patient is instructed not to have sex during the following 48 hours.The patient reports back 2.5 weeks later that he is now able topenetrate and have intercourse with his partner for up to about 15minutes without prematurely ejaculating, and these positive result areobserved for about 4 months, after which the patient returns for furtherbotulinum toxin administration. This time, the doctor administers thebotulinum toxin to the patient's frenulum utilizing a transdermalformulation of botulinum toxin type B. Positive results, with thepatient able to withstand intercourse for a minimum of about 9 minutesbefore ejaculation occurs, is reported.

Treatments according to the methods disclosed herein have manyadvantages, including:

-   1. effective relief of premature ejaculation, typically including at    least a doubling of a patient's climax baseline time, by utilizing a    relatively quick onset of effect, typically first noted from about    48 to about 72 hours after administration of botulinum neurotoxin;-   2. long term relief of premature ejaculation can be achieved, with    observed duration of effect being from about 3 months to about 6    months after administration of botulinum neurotoxin;-   3. there are no or minimal side effects from the practice of the    disclosed invention, and the methods are localized and do not entail    the ingestion and systemic circulation of pharmaceuticals that    heretofore have been utilized in treating premature ejaculation;-   4. use of the neurotoxins in accordance with the methods herein    disclosed results in no erectile dysfunction or loss of sensitivity,    unlike previously utilized methods for treating premature    ejaculation.

Although the present invention has been described in detail with regardto certain preferred methods, other embodiments, versions, andmodifications within the scope of the present invention are possible.For example, besides a botulinum toxin, other neurotoxins which canaccomplish the same desired result (treatment of premature ejaculationby local administration of the toxin) are within the scope of theinvention. Thus, a tetanus toxin can show efficacy as well asrecombinant, chimeric and modified Clostridial toxins, includingrecombinant, chimeric and modified botulinum toxins. Additionally, thepresent invention includes a treatment of premature ejaculation by localadministration of two or more neurotoxins, such as two or more botulinumtoxins, are administered concurrently or consecutively. For example,botulinum toxin type A can be administered until a loss of clinicalresponse or neutralizing antibodies develop, followed by administrationof botulinum toxin type B or E. Alternately, a combination of any two ormore of the botulinum serotypes A-G can be locally administered tocontrol the onset and duration of the desired therapeutic result.Furthermore, non-neurotoxin compounds can be administered prior to,concurrently with or subsequent to administration of the neurotoxin toproved adjunct effect such as enhanced or a more rapid onset ofdenervation before the neurotoxin, such as a botulinum toxin, begins toexert its therapeutic effect. Finally, use of a relatively short actingbotulinum toxin, such as a botulinum toxin type E, where use of a shortacting toxin is indicated, can also be utilized as herein disclosed totreat premature ejaculation, for example.

The terms “a,” “an,” “the” and similar referents used in the context ofdescribing the invention (especially in the context of the followingclaims) are to be construed to cover both the singular and the plural,unless otherwise indicated herein or clearly contradicted by context.Recitation of ranges of values herein is merely intended to serve as ashorthand method of referring individually to each separate valuefalling within the range. Unless otherwise indicated herein, eachindividual value is incorporated into the specification as if it wereindividually recited herein. All methods described herein can beperformed in any suitable order unless otherwise indicated herein orotherwise clearly contradicted by context. The use of any and allexamples, or exemplary language (e.g., “such as”) provided herein isintended merely to better illuminate the invention and does not pose alimitation on the scope of the invention otherwise claimed. No languagein the specification should be construed as indicating any non-claimedelement essential to the practice of the invention.

Groupings of alternative elements or embodiments of the inventiondisclosed herein are not to be construed as limitations. Each groupmember may be referred to and claimed individually or in any combinationwith other members of the group or other elements found herein. It isanticipated that one or more members of a group may be included in, ordeleted from, a group for reasons of convenience and/or patentability.When any such inclusion or deletion occurs, the specification is deemedto contain the group as modified thus fulfilling the written descriptionof all Markush groups used in the appended claims.

Variations of exemplary embodiments will become apparent to those ofordinary skill in the art upon reading the foregoing description. Theinventors expects skilled artisans to employ such variations asappropriate, and the inventors intend for the invention to be practicedotherwise than specifically described herein. For example, particulardoses and injection particulars such as number of administration sitesand locations of administration to the patient, useful in accordancewith the teachings of the present disclosure, are considered to bewithin the scope of the present invention. Accordingly, this inventionincludes all modifications and equivalents of the subject matter recitedin the claims appended hereto as permitted by applicable law. Moreover,any combination of the above-described elements in all possiblevariations thereof is encompassed by the invention unless otherwiseindicated herein or otherwise clearly contradicted by context.

Furthermore, numerous references have been made to patents and printedpublications throughout this specification. Each of the above-citedreferences and printed publications are individually incorporated hereinby reference in their entirety.

In closing, it is to be understood that the embodiments of the inventiondisclosed herein are illustrative of the principles of the presentinvention. Other modifications that may be employed are within the scopeof the invention. Thus, by way of example, but not of limitation,alternative configurations/methods of the present invention may beutilized in accordance with the teachings herein. Accordingly, thepresent invention is not limited to that precisely as shown anddescribed.

1. A method for treating premature ejaculation of a patient in needthereof, the method comprising the step of locally administering aClostridial neurotoxin to the patient, thereby treating prematureejaculation of the patient. 2 The method of claim 1, wherein localadministration of the therapeutic amount of Clostridial neurotoxin isaccomplished by transdermal, intramuscular, subcutaneous, subdermal,intradermal or implant administration.
 3. The method of claim 1, whereinlocal administration of the therapeutic amount of Clostridial neurotoxinis by injection.
 4. The method of claim 1, wherein the Clostridialneurotoxin is a botulinum neurotoxin.
 5. The method of claim 4, whereinthe botulinum neurotoxin is selected from the group consisting ofbotulinum neurotoxin types A, B, C, D, E, F and G.
 6. The method ofclaim 1, wherein the Clostridial neurotoxin is a botulinum neurotoxinand is administered in an amount of from about 1 unit to 20,000 units.7. The method of claim 1, wherein the Clostridial neurotoxin isbotulinum neurotoxin type A or type B, and is administered in an amountof from about 1 unit to 2500 units or from about 100 to about 10,000units, respectively.
 8. The method of claim 1, wherein the Clostridialneurotoxin is botulinum neurotoxin type A.
 9. The method of claim 1,wherein local administration of the therapeutic amount of theClostridial neurotoxin to the patient is accomplished via injection ofthe Clostridial neurotoxin into a penis of the patient.
 10. A method fortreating premature ejaculation in a patient in need thereof, the methodcomprising the step of locally administering by injection a botulinumneurotoxin to a penis of the patient, thereby treating prematureejaculation in the patient.
 11. The method of claim 10, wherein thebotulinum neurotoxin is botulinum neurotoxin type A.
 12. The method ofclaim 10, wherein the botulinum neurotoxin is injected into at least twopenile locations.
 13. The method of claim 10, wherein said localadministration is to a frenulum of the penis.
 14. The method of claim10, wherein the botulinum neurotoxin is a botulinum neurotoxin type Band the botulinum neurotoxin type B is administered in an amount between1 unit and about 10,000 units.
 15. A method for treating prematureejaculation in a patient in need thereof, the method comprising the stepof locally administering a botulinum neurotoxin type A to at least onelocation of a penis of the patient, thereby treating prematureejaculation in the patient.
 16. The method of claim 15, wherein anamount of botulinum neurotoxin type A administered to the penis is fromabout 1 unit to about 2500 units.
 17. The method of claim 16, whereinthe botulinum neurotoxin is administered to a frenulum or glans of thepenis.
 18. The method of claim 15, further comprising additionaladministration of botulinum neurotoxin to the penis of the patient leastabout 2 months after an initial administration of botulinum neurotoxinto the penis.
 19. The method of claim 15, wherein local administrationis by transdermal, intramuscular, subcutaneous, subdermal, intradermalor implant administration.
 20. The method of claim 15, wherein localadministration of the botulinum neurotoxin type A is from about 1 unitto about 500 units, per injection site, per patient visit.
 21. Themethod of claim 15, wherein the botulinum neurotoxin type A isadministered to a prepuce of the penis.
 22. A method for prolongation ofclimax time in a patient in need thereof, the method comprising the stepof locally administering a botulinum neurotoxin to the patent, therebyprorogating climax time in the patient.
 23. The method of claim 22,wherein local administration of the botulinum neurotoxin utilizestransdermal, intramuscular, subcutaneous, subdermal, intradermal orimplant administration.
 24. The method of claim 22, wherein localadministration of the botulinum neurotoxin is to a frenulum or prepuce.25. The method of claim 22, wherein local administration of thebotulinum neurotoxin is by injection and the botulinum neurotoxin isbotulinum neurotoxin type A or type B.